Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.
In: Journal of Medicinal Chemistry, Jg. 66 (2023-09-14), Heft 17
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Zugriff:
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease Mpro plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of Mpro. By comparing the efficacy of a panel of warheads installed on a common scaffold against Mpro, we discovered that the terminal alkyne could covalently modify Mpro as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of Mpro. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.
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Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.
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Autor/in / Beteiligte Person: | Fried, William ; Aliyari, Saba ; Feng, Joshua ; Qin, Chao ; Zhang, Shilei ; Yang, Hanjing ; Shanaa, Jean ; Feng, Pinghui ; Cheng, Genhong ; Chen, Xiaojiang ; Zhang, Chao ; Ngo, Chau |
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Zeitschrift: | Journal of Medicinal Chemistry, Jg. 66 (2023-09-14), Heft 17 |
Veröffentlichung: | eScholarship, University of California, 2023 |
Medientyp: | academicJournal |
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